Over the past several years it has become obvious to health professionals and the pharmaceutical industry that optimal therapy with existing drugs has not been achieved with conventional dosage forms (e.g., tablets, capsules, injectables, suppositories) and dosing regimens. The term "optimal therapy" means the safest, most rapid, and most convenient amelioration of any particular disease state. Further, the "safety" of the dosage form or dosing regimen refers to the frequency and severity of side reactions. Improvement in therapy can then be defined as any change in the dosage form or regimen for an existing drug that:
(1) reduces the frequency and severity of side reactions, PA1 (2) increases the rate at which cure or control is achieved, PA1 (3) decreases the degree of disruption of normal patient activities, and PA1 (4) enhances patient compliance with the prescribed regimen. PA1 Design A: 710 Microns - 1000 Microns PA1 Design B: 590 Microns - 840 Microns PA1 Design C: 500 Microns - 710 Microns
In response to this growing perception, a number of novel drug delivery systems have been developed and brought to market. Some good examples are the transdermal delivery devices such as Nitro-Dur.RTM. (Key Pharmaceuticals), Nitro-Disc.RTM.(Searle), Transderm Nitro.RTM. (Ciba), Catapres-TTS.RTM. (Boehringer-Ingelheim) and Transderm-Scop.RTM. (Ciba). Other examples are Theo-Dur.RTM. tablets (Key Pharmaceuticals), a sustained release form of theophylline, Theo-Dur.RTM. Sprinkle (U.S. Pat. No. 4,587,118) and Slo-Bid.TM. (Rorer) Theo-Dur.RTM. Sprinkle and Slo-Bid.TM. are microencapsulated forms of slow release theophylline that are intended for use in pediatric patients or other patients who may have difficulty in swallowing a tablet. The microcapsules ar supplied in hard gelatin capsules. The hard gelatin capsules are opened at the point of use by the care-giver and administered in a semi-solid food.
This form of drug delivery has significant drawbacks. First, there are a small finite number of capsule sizes marketed, and this limits the physician's ability to prescribe an appropriate dose on the basis of a particular patient's weight, severity of disease, and therapeutic response. Second, there is the possibility of tampering which has become a subject of major concern related to the safety of over-the-counter pharmaceutical products.
Flowable material dispensers such as that described in U.S. Pat. No. 4,579,256 were developed to overcome these drawbacks. The Flowable Material Dispenser is an adjustable, metering and dispensing package. The dispenser can accurately deliver a granular pharmaceutical product to a patient by pouring the selected dosage onto a small quantity of semi-solid food prior to swallowing. The semi-solid food may be contained on a spoon or in a cup. The dispenser is child-resistant, protects the product from the surrounding environment and precisely delivers an adjustable dose well within the compendial requirements for uniformity of dosage units. However, microgranules that are suitable for use in the Flowable Material Dispenser must meet certain narrow specifications with regard to average particle size, particle size distribution, shape, and active agent concentration. These specifications are defined as follows for prednisone microgranules:
Particle size/size distribution (depending on dispenser design):
______________________________________ Activity density greater than (potency .times. bulk density) 0.030 g/ml Appearance nearly spherical Flow freely flowing ______________________________________
Although an acceptable product could be made beyond the limits of these parameters, microgranule potency and size must interact to produce a particular activity density which insures that the smallest dose is contained in a volume that is reproducibly measurable while the largest dose is contained in a volume that is convenient to swallow. Small size is also essential if the particles are to be relatively impalpable when added to soft food.
High bulk density is also required if a dispenser of reasonable size for one hand operation is to contain a ten to sixty day supply of drug. Narrow size distribution insures reproducibility of each measured dose and eliminates variation in bulk density due to segregation of sizes. This is critical to a device which measures solid particles by volume. Narrow particle size distribution also implies reproducibility of bulk density from batch to batch. Thus, the same volume will contain the same amount of drug every time in production, which is a new requirement, imposed by the flowable material dispenser but not by conventional delivery systems like hard gelatin capsules. It is also important that the microgranules be nearly spherical to impart the flow characteristics that are required at every stage of assembly and use of the dispenser. The nearly spherical aspect of the microgranules also enhances product elegance.
Presently available conventional pharmaceutically active granules are generally inappropriate for oral administration with semi-solid food or for use in a hand-held flowable material dispenser. These conventional granules are large and create a noticeable gritty mouthfeel for the patient. Large microgranule size also necessitates an increase in the smallest characteristic dimension of the measuring cylinder, and the flow channels of the flowable material dispenser if particle bridging is to be avoided. An increase in the smallest characteristic dimension of the measuring cylinder is also necessary if the requirements of the United States Pharmacopeia for Uniformity of Dosage Units are to be met. As those characteristic dimensions increase, so does the overall size of the flowable material dispenser. Each increase in size of the dispenser results in the loss of a degree of convenience in its use. At some microgranule size larger than 18 mesh (1000 microns), the flowable material dispenser becomes too large to be comfortably hand-held and hand-operated. Conventional granules are also difficult to accurately dispense from a hand-held flowable material dispenser due to the broad size distribution of granules both within and between batches, as well as the lack of uniform shape of the conventional granules.
Additionally, most pharmaceutically active agents have an unpleasant taste, and many such agents are administered to children who have more taste buds on their tongues than adults and are therefore more cognizant of unpleasant tastes (Remington's Pharmaceutical Sciences 15th ed., 1226 (1975)). Some of the pharmaceutically active agents with a more notorious reputation for unpleasant taste include dicloxacillin, erythromycin, cephalosporins and prednisone.
Numerous attempts to mask these unpleasant tastes in conventional dosage forms such as tablets, solutions, and suspensions follow the conventional wisdom of attempting to overpower the unpleasant flavor with a more pleasant one. For example, salty tastes are conventionally masked by syrups such as cinnamon syrup, orange syrup and cherry syrup; bitter tastes are conventionally masked by syrups such as cocoa syrup, raspberry syrup and cherry syrup; acrid or sour tastes are conventionally masked by syrups such as raspberry syrup and acacia syrup; and oily tastes are conventionally masked by syrups such as aromatic rhubarb syrup, compound sarsaparilla syrup and lemon syrup. These conventional taste-masking techniques were more often than not less than satisfactory, particularly in the case of children's medicines.
Prednisone is uniquely suited for incorporation into a flowable material dispenser because a number of important new therapeutic uses are coming to the fore, and the presently available dosage forms are inadequate for the treatment of children in any condition. The presently marketed tablets are too large to be swallowed by children, and the liquids are unpalatable. Similarly, when tablets are crushed to allow easier swallowing the taste is so objectionable that leukemic children have been known to refuse to comply with the prescribed regimen. It is becoming known that hospitalizations due to acute asthma can be significantly reduced by the use of prednisone prophylactically. That is, when an asthmatic child gets a cold, more and more physicians are going to be recommending burst therapy to prevent an attack. At present, 15% of all hospitalizations are due to asthma. Additionally, recent publications suggest that prednisone will be used in combination with antibiotics in otitis media and otitis media with effusion. Given this increasing use of prednisone in seriously ill children, life-threatening treatment failures can be expected unless a more palatable form of the drug is developed. It is this problem that the present invention is intended to eliminate.